The loss of contractile myocardium resulting from the destruction of cardiac cells and extracellular matrix is the hallmark of myocardial infarction (MI). The consequence of a large MI or repeated MI?s is progressive enlargement of the left ventricle, chronic heart failure and death. Heart transplant can save lives; however, critical whole organ shortages prevent wide adoption of this therapy. Therefore, post MI heart failure continues to be a major public health challenge. Cell-based therapy has evolved as a tantalizing, regenerative medicine, approach to prevent post-MI remodeling; however, clinical trials using bone marrow, adipose, skeletal muscle and adult cardiac-derived cells have shown no or only modest benefit. Poor cell retention, failure to replace cardiomyocytes and to replenish cardiac extracellular matrix are critical barriers in the field. We propose a therapeutic solution to remuscularize the myocardium using an innovative population of human iPSC-derived committed cardiac progenitors (CCPs) in combination with a natural cardiac fibroblast-derived extracellular matrix (cECM) to improve cell retention and restore damaged matrix. CCPs have an extraordinary ability to become cardiomyocytes that integrate in damaged myocardium. cECM binds to therapeutic cells and improves their retention in cardiac tissue. In addition, preliminary data suggests cECM improves the health of the myocardium through immunomodulation, angiogenesis and matrix replacement. Both CCPs and cECM can be manufactured to narrow specifications and high scale. We hypothesize that intramuscular co-administration of CCP combined with cECM will remuscularize the myocardium and improve cardiac function more effectively than either product alone. To test this hypothesis, we will measure the efficacy and safety of this approach in a clinically representative pig post-MI chronic heart failure model. First, pigs will undergo a coronary artery balloon occlusion and reperfusion MI, followed 4 weeks later by minimally invasive, transendocardial injection of CCPs + cECM, CCPs alone, cECM alone or sham. Contractility, chamber geometry, viability and strain analysis will be performed using quantitative magnetic resonance imaging. Detailed histopathology will be performed. A continuous ECG recorder will be implanted for arrhythmia surveillance. The primary efficacy endpoint will be change in ejection fraction from baseline to 3 months. Highly qualified investigators at the University of Wisconsin-Madison will partner with Fujifilm Cellular Dynamics Inc., Madison, WI (manufacturers of CCPs) and Cellular Logistics Inc., Sun Prairie, WI (manufacturer of cECM, also known as CellogicusTM) to ensure careful scientific rigor is applied for this Investigational New Drug (IND) enabling project. The design of this study has been carefully considered in accordance to FDA/CBER guidelines and will benefit from continued guidance through the Regenerative Medicine Innovation Catalyst to accelerate therapeutic product development and inform future human trials.